System and method of extracorporeally treating blood to alleviate the symptoms of inflammatory diseases

ABSTRACT

An extracorporeal blood circulation system for treating inflammatory diseases includes a blood collection device for collecting blood from a patient suffering from an inflammatory disease, an anticoagulant mixing device for mixing an anticoagulant into the collected blood, blood transportation device for transporting the anticoagulant-containing blood at a flow rate in the range of from 20 to 200 ml/minute, a blood treating device having a blood inlet and a blood outlet and containing a platelet activating device, and a blood returning device for returning the treated blood to the patient, each being liquid-tightly connected in this order through a tubing so that when extracorporeal blood circulation is conducted using the system with respect to blood from the patient, the system is capable of providing treated blood satisfying at least one requirement selected from requirement (1) of having a β-thromboglobulin concentration in the range of from 1,000 to 20,000 ng/ml and requirement (2) of having a platelet factor 4 concentration in the range of from 500 to 10,000 ng/ml. Also disclosed is an extracorporeal blood circulation method which provides treated blood in which platelets are activated to a specific degree that the above-mentioned requirement (1) and/or requirement (2) is satisfied and so as to achieve a high therapeutic effect on inflammatory diseases.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to an extracorporeal blood circulationsystem for treating inflammatory diseases. More particularly, thepresent invention is concerned with an extracorporeal blood circulationsystem for treating inflammatory diseases, which has a construction suchthat, when extracorporeal blood circulation is conducted using thesystem with respect to blood from a patient, the system is capable ofproviding treated blood in which platelets are activated to a specificdegree. By the use of the extracorporeal blood circulation system of thepresent invention, a high therapeutic effect on inflammatory diseasescan be achieved, as compared to a therapeutic effect achieved byconventional extracorporeal blood circulation therapies (such asplasmapheresis and a method using a leukocyte trapping filter).

2. Prior Art

An inflammatory disease is a disease in which an infiltration ofleukocytes into a diseased site occurs, or a disease in which aninflammation markedly occurs due to active oxygen and various cytokineswhich are released from leukocytes.

Ulcerative colitis and Crohn's disease are chronic inflammatory diseasesof the digestive tract. Currently, ulcerative colitis is generallybelieved to be a cryptogenic disease; however, it has been suspectedthat ulcerative colitis is attributable to an antilarge intestineantibody, an autoimmune T cell and the like.

Methods for treating these diseases can be classified intointernal-medical treatment and surgical treatment. In aninternal-medical treatment, drugs are used for the treatment, whereinsuch drugs are appropriately selected in accordance with the degree ofseriousness of the symptoms and the location of the ulcer. Examples ofsuch drugs include salazosulfapyridine (manufactured and sold by TheGreen Cross Corporation, Japan), prednisolone (manufactured and sold byShionogi & Co., Ltd., Japan), azathioprine (manufactured and sold bySumitomo Pharmaceuticals Co., Ltd., Japan and Nippon Wellcome K. K.,Japan) and tranilast (manufactured and sold by KISSEI PHARMACEUTICALCO., LTD., Japan). Such internal-medical treatments are effective formost cases of ulcerative colitis; however, the use of a drug fortreating ulcerative colitis poses the danger of the occurrence of a sideeffect.

In a surgical treatment, excision of the diseased site is performed by asurgical operation. However, with respect to Crohn's disease, after theexcision, the probability of the recurrence of the disease is high.Further, with respect to both of ulcerative colitis and Crohn's disease,after the excision, it is frequently necessary that the patient befitted with an artificial anus, inevitably leading to a lowering of thequality of life (QOL).

Articular rheumatism is a cryptogenic generalized inflammatory diseasein which the cardinal symptom is polyarthritis, and which may alsoexhibit various extra-articular symptoms, such as subcutaneous nodule,angiitis, pleurisy and diffuse interstitial pneumonia. It has been knownthat an autoantibody, which is called a rheumatoid factor, is present inserum and synovia from a patient suffering from articular rheumatism.

For treating this disease (articular rheumatism), various drugs are usedin combination, wherein such drugs are selected from, for example, anon-steroidal anti-inflammatory drug, a steroidal drug, animmunosuppressant and an immunomodulator. A treatment using drugs iseffective for most patients suffering from articular rheumatism;however, this treatment poses the danger of the occurrence of a sideeffect. With respect to inflammatory diseases which do not favorablyrespond to any drug or which cannot be treated with drugs due to seriousside effects of the drugs, it has been reported that such inflammatorydiseases have been effectively treated by using plasmapheresis, such asdouble filtration plasmapheresis and immunoadsorption plasmapheresis.Plasmapheresis is a therapeutic method in which a rheumatoid factor andan immune complex, both which are thought to be causative ofinflammation, are removed from the patient. {With respect toplasmapheresis, reference can be made to, for example, the followingliterature: Y. Itakura et al., Effects of Double FiltrationPlasmapheresis for Rheumatoid Arthritis, p.133-136, TherapeuticPlasmapheresis (VII), Proceedings of the Seventh Symposium onTherapeutic Plasmapheresis, Tokyo, Jun. 5-6, 1987, Japanese Society forTherapeutic Plasmapheresis; N. Kobayashi et al., Plasma Cleaning UsingImmunoadsorbent IM-P for Patients with Rheumatoid Arthritis, p.153-157,Therapeutic Plasmapheresis (IV), Proceedings of the 4th Symposium onTherapeutic Plasmapheresis, Tokyo, Jun. 2nd, 1984, Japanese Society forTherapeutic Plasmapheresis. } However, the convntional techniques ofplasmapheresis are unsatisfactory in therapeutic effect. It is desiredto improve the therapeutic effect of plasmapheresis.

In recent years, it has been suggested that inflammatory diseases (suchas ulcerative colitis and articular rheumatism) can be treated byreducing the number of leukocytes present in the blood of a patient,using a device comprising a fibrous filter (see European PatentApplication Publication No. 478,914, Pall Corporation). Further, thereis also a report that, when a patient suffering from articularrheumatism was subjected to a lymphocyte removal therapy, the symptomsof the patient were alleviated (Artificial Organs, Vol. 15, No. 3,1991).

However, the alleviation of clinical symptoms accompanying inflammatorydiseases, which can be achieved by an extracorporeal blood circulationusing a known leukocyte trapping filter, is at best similar to thatobtained by plasmapheresis. Therefore, it is desired to improve thetherapeutic effect of the extracorporeal blood circulation therapy.

SUMMARY OF THE INVENTION

In this situation, the present inventors have made extensive andintensive studies with a view toward developing a method for treatinginflammatory diseases, which can achieve a high therapeutic effect, ascompared to a therpeutic effect achieved by the conventional therapeuticmethods. As a result, the following has unexpectedly been found.Conventionally, in performing a therapeutic method in which blood istaken out of the body of a patient and the blood is treated and thenreturned to the body of the patient (i.e., in performing anextracorporeal blood circulation therapy), it has been an establishedknowledge that, as materials for equipment used in the therapy (e.g., amaterial for a tubing used for extracorporeal blood circulation and amaterial for a blood treating element), use should be made of thosematerials which are as excellent as possible in the ability to avoidactivation of the coagulation system (including platelets), thecomplement system and the like with respect to the blood. However, inconnection with the therapy of inflammatory diseases, the presentinventors have made a quite surprising finding which overturns suchconventional knowledge in the field of the extracorporeal bloodcirculation methods for treating diseases. Specifically, the presentinventors have found that, in an extracorporeal blood circulation methodfor treating inflammatory diseases, a high therapeutic effect can beachieved by activating platelets in the extracorporeally circulatedblood to a degree that treated blood satisfies at least one requirementselected from the group consisting of the following requirements (1) and(2):

(1) having a β-thromboglobulin concentration in the range of from 1,000to 20,000 ng/ml, as measured just outside of a blood outlet of bloodtreating means; and

(2) having a platelet factor 4 concentration in the range of from 500 to10,000 ng/ml, as measured just outside of a blood outlet of bloodtreating means.

The present invention has been completed, based on the above novelfinding.

Accordingly, it is an object of the present invention to provide anextracorporeal blood circulation system for treating inflammatorydiseases, which is capable of providing treated blood in which plateletsare activated to a specific degree, thereby achieving a high therapeuticeffect on inflammatory diseases, as compared to a therapeutic effectachieved by conventional extracorporeal blood circulation systems fortreating inflammatory diseases.

It is another object of the present invention to provide anextracorporeal blood circulation method for treating inflammatorydiseases, which is capable of providing treated blood in which plateletsare activated to a specific degree, thereby achieving a high therapeuticeffect on inflammatory diseases, as compared to a therapeutic effectachieved by conventional extracorporeal blood circulation methods fortreating inflammatory diseases.

The foregoing and other objects, features and advantages of the presentinvention will be apparent from the following detailed description takenin connection with the accompanying drawing and the appended claims.

BRIEF DESCRIPTION OF THE DRAWING

In the drawing:

FIG. 1. is a diagram showing an example of the extracorporeal bloodcirculation system of the present invention.

Description of the reference numerals:

1: Means for collecting blood from a patient

2: Means for mixing an anticoagulant into the collected blood

2A: Anticoagulant

3: Means for transporting the anticoagulant-containing blood

4: Blood treating means containing platelet activating means

4A: Platelet activating means

5: Means for returning the treated blood to the patient

6: Microaggregate trapping means

6A: Arterial pressure monitor

7: Drip chamber

7A: Venous pressure monitor

DETAILED DESCRIPTION OF THE INVENTION

In one aspect of the present invention, there is provided anextracorporeal blood circulation system for treating inflammatorydiseases, comprising:

blood collection means for collecting blood from a patient sufferingfrom an inflammatory disease,

anticoagulant mixing means for mixing an anticoagulant into thecollected blood, the anticoagulant having the ability to suppress anincrease in concentration of at least one platelet factor in thecollected blood, the at least one platelet factor being selected fromthe group consisting of β-thromboglobulin and platelet factor 4,

blood transportation means for transporting the anticoagulant-containingblood at a flow rate in the range of from 20 to 200 ml/minute,

blood treating means having a blood inlet and a blood outlet andcontaining platelet activating means having the ability to increase,upon treatment of blood with the blood treating means, the concentrationof the at least one platelet factor in the blood, and

blood returning means for returning the treated blood to the patient,

the blood collection means, the anticoagulant mixing means, the bloodtransportation means, the blood treating means and the blood returningmeans being liquid-tightly connected in this order through a tubing,

wherein, when extracorporeal blood circulation is conducted using thesystem with respect to blood from the patient, the system is capable ofproviding treated blood satisfying at least one requirement selectedfrom the group consisting of the following requirements (1) and (2):

(1) having a β-thromboglobulin concentration in the range of from 1,000to 20,000 ng/ml, as measured just outside of the blood outlet of theblood treating means; and

(2) having a platelet factor 4 concentration in the range of from 500 to10,000 ng/ml, as measured just outside of the blood outlet of the bloodtreating means.

In another aspect of the present invention, there is provided anextracorporeal blood circulation method for treating inflammatorydiseases, comprising:

collecting blood from a patient suffering from an inflammatory disease,

mixing an anticoagulant into the collected blood, the anticoagulanthaving the ability to suppress an increase in concentration of at leastone platelet factor in the collected blood, the at least one plateletfactor being selected from the group consisting of β-thromboglobulin andplatelet factor 4,

transporting the blood having the anticoagulant mixed thereinto at aflow rate in the range of from 20 to 200 ml/minute to blood treatingmeans having a blood inlet and a blood outlet and containing plateletactivating means having the ability to increase, upon treatment of bloodwith the blood treating means, the concentration of the at least oneplatelet factor in the blood,

passing the blood through the blood treating means from the inlet to theoutlet to treat the blood, and

returning the treated blood to the patient,

the treated blood satisfying at least one requirement selected from thegroup consisting of the following requirements (1) and (2):

(1) having a β-thromboglobulin concentration in the range of from 1,000to 20,000 ng/ml, as measured just outside of the blood outlet of theblood treating means; and

(2) having a platelet factor 4 concentration in the range of from 500 to10,000 ng/ml, as measured just outside of the blood outlet of the bloodtreating means.

For an easy understanding of the present invention, the essentialfeatures and various preferred embodiments of the present invention areenumerated below.

1. An extracorporeal blood circulation system for treating inflammatorydiseases, comprising:

blood collection means for collecting blood from a patient sufferingfrom an inflammatory disease,

anticoagulant mixing means for mixing an anticoagulant into thecollected blood, the anticoagulant having the ability to suppress anincrease in concentration of at least one platelet factor in thecollected blood, the at least one platelet factor being selected fromthe group consisting of β-thromboglobulin and platelet factor 4,

blood transportation means for transporting the anticoagulant-containingblood at a flow rate in the range of from 20 to 200 ml/minute,

blood treating means having a blood inlet and a blood outlet andcontaining platelet activating means having the ability to increase,upon treatment of blood with the blood treating means, the concentrationof the at least one platelet factor in the blood, and

blood returning means for returning the treated blood to the patient,

the blood collection means, the anticoagulant mixing means, the bloodtransportation means, the blood treating means and the blood returningmeans being liquid-tightly connected in this order through a tubing,

wherein, when extracorporeal blood circulation is conducted using thesystem with respect to blood from the patient, the system is capable ofproviding treated blood satisfying at least one requirement selectedfrom the group consisting of the following requirements (1) and (2):

(1) having a β-thromboglobulin concentration in the range of from 1,000to 20,000 ng/ml, as measured just outside of the blood outlet of theblood treating means; and

(2) having a platelet factor 4 concentration in the range of from 500 to10,000 ng/ml, as measured just outside of the blood outlet of the bloodtreating means.

2. The extracorporeal blood circulation system according to item 1above, wherein the blood treating means is a module comprising a casinghaving a blood inlet and a blood outlet, and said platelet activatingmeans packed therein, the platelet activating means comprising amaterial comprised mainly of at least one member selected from the groupconsisting of fibers, a porous material, particles, a film, a planarmembrane, a hollow fiber membrane and a tubular material.

3. The extracorporeal blood circulation system according to item 1above, wherein the blood treating means has a pressure drop index in therange of from 20 to 150, wherein the pressure drop index is defined as avalue obtained by a method in which heparin is added to bovine bloodhaving a hematocrit value of about 40% and a total protein of about 6.5g/dl of plasma so that a final heparin concentration becomes 5 units (inaccordance with the meaning of a unit as defined in the 12th RevisedJapanese Pharmacopeia) per ml of the bovine blood; the bovine blood isflowed through the blood treating means at a flow rate of 50 ml/minute,wherein, before the bovine blood enters the blood treating means, thesame anticoagulant as used in a treatment of the patient with theextracorporeal blood circulation system is mixed into the bovine bloodin the same manner as in the treatment of the patient; a blood pressuredifference (mmHg) as between the blood inlet and blood outlet of theblood treating means is measured 20 minutes after the start of theflowing of the bovine blood; and the blood pressure difference is takenas a pressure drop index.

4. The extracorporeal blood circulation system according to item 1above, wherein the platelet activating means is capable of removingleukocytes.

5. An extracorporeal blood circulation method for treating inflammatorydiseases, comprising:

collecting blood from a patient suffering from an inflammatory disease,

mixing an anticoagulant into the collected blood, the anticoagulanthaving the ability to suppress an increase in concentration of at leastone platelet factor in the collected blood, the at least one plateletfactor being selected from the group consisting of β-thromboglobulin andplatelet factor 4,

transporting the blood having the anticoagulant mixed thereinto at aflow rate in the range of from 20 to 200 ml/minute to blood treatingmeans having a blood inlet and a blood outlet and containing plateletactivating means having the ability to increase, upon treatment of bloodwith the blood treating means, the concentration of the at least oneplatelet factor in the blood,

passing the blood through the blood treating means from the inlet to theoutlet to treat the blood, and

returning the treated blood to the patient,

the treated blood satisfying at least one requirement selected from thegroup consisting of the following requirements (1) and (2):

(1) having a β-thromboglobulin concentration in the range of from 1,000to 20,000 ng/ml, as measured just outside of the blood outlet of theblood treating means; and

(2) having a platelet factor 4 concentration in the range of from 500 to10,000 ng/ml, as measured just outside of the blood outlet of the bloodtreating means.

6. The extracorporeal blood circulation method according to item 5above, wherein the blood treating means is a module comprising a casinghaving a blood inlet and a blood outlet, and said platelet activatingmeans packed therein, the platelet activating means comprising amaterial comprised mainly of at least one member selected from the groupconsisting of fibers, a porous material, particles, a film, a planarmembrane, a hollow fiber membrane and a tubular material.

7. The extracorporeal blood circulation method according to item 5above, wherein the blood treating means has a pressure drop index in therange of from 20 to 150, wherein the pressure drop index is defined as avalue obtained by a method in which heparin is added to bovine bloodhaving a hematocrit value of about 40% and a total protein of about 6.5g/dl of plasma so that a final heparin concentration becomes 5 units (inaccordance with the meaning of a unit as defined in the 12th RevisedJapanese Pharmacopeia) per ml of the bovine blood; the bovine blood isflowed through the blood treating means at a flow rate of 50 ml/minute,wherein, before the bovine blood enters the blood treating means, thesame anticoagulant as used in a treatment of the patient with theextracorporeal blood circulation system is mixed into the bovine bloodin the same manner as in the treatment of the patient; a blood pressuredifference (mmHg) as between the blood inlet and blood outlet of theblood treating means is measured 20 minutes after the start of theflowing of the bovine blood; and the blood pressure difference is takenas a pressure drop index.

8. The extracorporeal blood circulation method according to item 5above, wherein the platelet activating means is capable of removingleukocytes.

Hereinbelow, the present invention will be explained in more detail withreference to FIG. 1.

FIG. 1 is a diagram showing an example of the extracorporeal bloodcirculation system of the present invention. The extracorporeal bloodcirculation system shown in FIG. 1 comprises means 1 for collectingblood from a patient suffering from an inflammatory disease, means 2 formixing anticoagulant 2A with the collected blood, means 3 fortransporting the anticoagulant-containing blood at a flow rate in therange of from 20 to 200 ml/minute, microaggregate trapping means 6having arterial pressure monitor 6A, blood treating means 4 having ablood inlet and a blood outlet and containing platelet activating means4A, drip chamber 7 having venous pressure monitor 7A and means 5 forreturning the treated blood to the patient are liquid-tightly connectedin this order through a tubing. Examples of means 1 for collecting bloodfrom a patient suffering from an inflammatory disease include a needleand a catheter which are used in known extracorporeal blood circulationapparatuses. As an example of blood transportation means 3, there can bementioned a blood transportation pump (such as a peristaltic pump) usedin a known extracorporeal blood circulation apparatus. When such a knownblood transportation pump is used as blood transportation means 3 of theextracorporeal blood circulation system, it is preferred that a tubingused in the pump has a relatively small inner diameter, from theviewpoint of preventing the blood entering the platelet activating meansfrom assuming a pulsating flow. The flow rate for the bloodtransportation is appropriately selected in the range of from 20 to 200ml/minute, wherein the selected flow rate is desired to be, for example,a value such that the burden of the flow rate on the patient is as smallas possible in respect of both the blood collection and blood return,and that clogging of, e.g., the blood treating means withmicroaggregates does not occur.

As an example of means 2 for mixing anticoagulant 2A into the collectedblood, there can be mentioned a known infusion pump which can feed intothe collected blood an anticoagulant stored in a container. When a lowmolecular weight heparin or the like is used as the anticoagulant, themeans for mixing an anticoagulant into the collected blood may be adevice which can be used for directly feeding into the collected bloodan anticoagulant without using a pump. The feeding of an anticoagulantinto the collected blood may also be performed by using a pressure head,instead of a pump. Further, when a drip chamber as mentioned below isused in the blood circulation system, it is preferred that theanticoagulant is fed into the collected blood at a position in thesystem on a side upstream of the drip chamber, as viewed in the flowdirection of the collected blood. When the anticoagulant is fed into thecollected blood at a position in the system on a side upstream of thedrip chamber, the resultant mixture of the anticoagulant and the bloodis temporarily pooled in the drip chamber, so that a more improvedmixing of the anticoagulant into the blood can be achieved, leading to areduction in a danger such that blood coagulation causes a clogging ofthe platelet activating means contained in the blood treating meanspositioned downstream of the drip chamber. It is also preferred thatdrip chamber 7 equipped with a mesh is provided downstream of bloodtreating means 4, as shown in FIG. 1.

Generally, in the extracorporeal blood circulation therapies, asanticoagulant, use is made of Acid-Citrate-Dextrose A solution(hereinafter, frequently referred to simply as "ACD-A solution"),heparin (including a low molecular weight heparin), nafamostat mesilate,gabexate mesilate or the like. In the present invention, any of theseknown anticoagulants can be used. An ACD-A solution is generally used inan amount such that the (anticoagulant/blood) volume ratio falls in therange of from 1:15 to 1:5. Anticoagulants other than ACD-A solution areused in an amount such that the (anticoagulant/blood) volume ratio fallsin the range of from about 1:3,000 to about 1:1,000. Thus, in the caseof the use of anticoagulants other than ACD-A solution, the proportionof blood in the total volume of the anticoagulant and blood is veryhigh, so that it is not easy to achieve a satisfactory mixing betweenthe anticoagulant and blood. Therefore, for achieving a better mixing ofan anticoagulant other than ACD-A solution into blood, a method may beemployed in which an anticoagulant other than ACD-A solution ispreliminarily diluted with a physiological solution and then, thediluted anticoagulant is continuously fed into the blood during theextracorporeal blood circulation. With respect to the amount of aphysiological solution used for diluting the anticoagulant (in order toachieve a better mixing of the anticoagulant into blood), the amount ofa physiological solution is appropriately chosen, taking intoconsideration a balance between the suppression of the occurrence ofclogging in the system and the prevention of a heavy burden on thepatient due to the introduction of too large an amount of aphysiological solution into the patient. In general, it is preferredthat the anticoagulant is diluted 100-fold to 300-fold with aphysiological solution. As examples of physiological solutions, therecan be mentioned a physiological saline exhibiting an osmotic pressureof from 200 to 400 mOsm, preferably from 280 to 300 mOsm, and a 5 w/v %(5 g/dl) aqueous glucose solution.

In the present invention, with respect to the structure of bloodtreatment means 4 having a blood inlet and a blood outlet and containingplatelet activating means 4A having the ability to increase, upontreatment of blood with the blood treating means, the concentration ofthe above-mentioned at least one platelet factor in the blood, there isno particular limitation. However, not preferred is a structure whichsignificantly activates blood coagulation factors other thanβ-thromboglobulin and platelet factor 4, leading to the occurrence ofcoagulation of the treated blood. As mentioned below, examples of bloodtreating means containing platelet activating means, which areemployable in the present invention, include a module comprising acasing having a blood inlet and a blood outlet, and platelet activatingmeans packed therein, wherein the platelet activating means comprises amaterial comprised mainly of at least one member selected from the groupconsisting of fibers, a porous material, particles, a film, a planarmembrane, a hollow fiber membrane and a tubular material.

When extracorporeal blood circulation is conducted using theextracorporeal blood circulation system of the present invention, thesystem is so constructed as is capable of providing treated bloodsatisfying at least one requirement selected from the group consistingof the following requirements (1) and (2):

(1) having a β-thromboglobulin concentration in the range of from 1,000to 20,000 ng/ml, as measured just outside of the blood outlet of theblood treating means after about 1.5 litters of blood has been treatedby the system from the start of the extracorporeal blood circulation;and

(2) having a platelet factor 4 concentration in the range of from 500 to10,000 ng/ml, as measured just outside of the blood outlet of the bloodtreating means after about 1.5 litters of blood has been treated by thesystem from the start of the extracorporeal blood circulation.

A platelet has a platelet granule therein, and the platelet granulecontains platelet factor 4, β-thromboglobulin, serotonin and the like.When a platelet is activated by some stimulation, it undergoes a releasereaction which causes the above-mentioned substances contained in theplatelet granule to be released out of the platelet. With respect to thefunction of platelet factor 4, it is known that platelet factor 4specifically binds to heparin to neutralize the anticoagulation activityof heparin. With respect to the function of β-thromboglobulin, it isknown that β-thromboglobulin has an antagonistic activity againsturokinase. Urokinase is one of plasminogen activators, which activateplasminogen to induce conversion of plasminogen into plasmin which has athrombolysis activity. Accordingly, β-thromboglobulin inhibitsthrombolysis due to its antagonism against urokinase.

With respect to the mechanism of the unexpected phenomenon that, in anextracorporeal blood circulation method for treating inflammatorydiseases, a high therapeutic effect can be achieved by activatingplatelets in the extracorporeally circulated blood to a specific degree,complete elucidation of the mechanism of this unexpected phenomenon,which overturns conventional knowledge in the art, has not yet beenmade. However, it is presumed that, by activating platelets to aspecific degree, neutrophile chemotactic factors (such as plateletfactor 4) are released from platelets, and the released neutrophilechemotactic factors cause neutrophiles to wander out of the inflamedsite to thereby reduce the neutrophile concentration at and around theinflamed site, leading to the suppression of the inflammation.

In the blood of a healthy person, the β-thromboglobulin concentration isabout 20 to about 40 ng/ml and the platelet factor 4 concentration isabout 7 to about 20 ng/ml. Therefore, when the β-thromboglobulinconcentration does not reach 1,000 ng/ml and/or the platelet factor 4concentration does not reach 500 ng/ml, it means that platelets in theblood are in a slightly activated state, as compared to platelets in theblood of a healthy person; however, since these concentration values arelower than the respective ranges of the above-mentioned requirements (1)and (2) defined in the present invention, the excellent therapeuticeffects of the present invention cannot be achieved. Specifically, withrespect to a patient suffering from an inflammatory disease, when boththe β-thromboglobulin concentration and the platelet factor 4concentration are lower than the respective ranges of theabove-mentioned requirements (1) and (2) defined in the presentinvention, it is expected that the amount of neutrophile chemotacticfactors released from platelets is unsatisfactorily small, whereinexamples of neutrophile chemotactic factors include platelet factor 4,12-L-hydroxy-5,8,10,14-eicosatetraenoic acid and12-L-hydroxy-5,8,10-heptadecatrienoic acid. Therefore, in this case, alowering of the neutrophile concentration at or around an inflamed sitedose not occur, so that the excellent effects of the present inventioncannot be exhibited, that is, a high degree of alleviation of theclinical symptoms of an inflammatory disease cannot be expected. On theother hand, when treated blood has too high a β-thromboglobulinconcentration and too high a platelet factor 4 concentration, bloodcoagulation is likely to proceed, so that the blood circulation systemis clogged with coagulated blood and it becomes impossible to use theblood circulation system. Therefore, in the extracorporeal bloodcirculation system of the present invention, it is requisite that thesystem be constructed so as to be capable of providing treated bloodsatisfying at least one requirement selected from the group consistingof requirement (1) of having a β-thromboglobulin concentration in therange of from 1,000 to 20,000 ng/ml, as measured just outside of theblood outlet of the blood treating means, and requirement (2) of havinga platelet factor 4 concentration in the range of from 500 to 10,000ng/ml, as measured just outside of the blood outlet of the bloodtreating means.

It is preferred that the β-thromboglobulin concentration is in the rangeof from 1,500 to 20,000 ng/ml, more preferably from 2,000 to 20,000ng/ml, most preferably from 3,000 to 20,000 ng/ml.

It is preferred that the platelet factor 4 concentration is in the rangeof from 750 to 10,000 ng/ml, more preferably from 900 to 10,000 ng/ml,most preferably from 1,500 to 10,000 ng/ml.

For achieving the excellent effects of the present invention, it isnecessary to activate platelets to a degree that at least one of theabove-mentioned β-thromboglobulin concentration requirement (1) and theplatelet factor 4 concentration requirement (2) is satisfied, and it isnot necessary that both of the β-thromboglobulin concentrationrequirement (1) and the platelet factor 4 concentration requirement (2)are satisfied. However, in general, when platelets are activated, thereis a tendency that the β-thromboglobulin concentration and plateletfactor 4 concentration are simultaneously elevated.

In the present invention, each of the β-thromboglobulin concentrationand platelet factor 4 concentration is measured with respect to a bloodsample taken at a position in the system just outside of the bloodoutlet of the blood treating means. Each of these concentration valuescan be measured by, for example, enzyme immunoassay (hereinafter,frequently referred to simply as "EIA").

In the present invention, platelets present in the collected blood areactivated to a specific degree that the above-mentioned requirement (1)and/or requirement (2) is satisfied. The activation of platelets to sucha specific degree can be achieved as a total effect of both of:

anticoagulant 2A having the ability to suppress an increase inconcentration of at least one platelet factor in the collected blood,wherein the above-mentioned at least one platelet factor is selectedfrom the group consisting of β-thromboglobulin and platelet factor 4,and

blood treating means 4 containing platelet activating means having theability to increase, upon treatment of blood with the blood treatingmeans, the concentration of the above-mentioned at least one plateletfactor in the blood.

With respect to the structure of the blood treating means, there is noparticular limitation as long as platelets can be activated to aspecific degree that the above-mentioned requirement (1) and/orrequirement (2) is satisfied. In the present invention, as a preferredexample of blood treating means, there can be mentioned a modulecomprising a casing having a blood inlet and a blood outlet, andplatelet activating means packed therein, wherein the plateletactivating means comprises a material comprised mainly of at least onemember selected from the group consisting of fibers, a porous material,particles, a film, a planar membrane, a hollow fiber membrane and atubular material. Specific examples of the above-mentioned moduleinclude:

a module comprising a casing and, packed therein, a depth filter whichis comprised of a fibrous or porous material having narrow gaps throughwhich blood can pass;

a module comprising a column and, packed therein, particles, beads orthe like; and

a module comprising a casing and, packed therein, a bundle of poroushollow fiber membranes.

Examples of materials for the above-mentioned fibers, particles and filminclude a polyester, polypropylene, a polyamide, polyethylene,polyacrylonitrile, cellulose acetate, polystyrene, a polysulfone, aglass and a ceramic. Examples of materials for the above-mentionedplanar membrane and hollow fiber membrane include polyacrylonitrile,cellulose acetate, polymethyl methacrylate, a polysulfone, cellulose andethylene vinyl alcohol. Examples of materials for the above-mentionedtubular material include polyvinyl chloride, a silicone rubber and apolyurethane. Examples of materials for the above-mentioned porousmaterial include a polyurethane, a polyester and polyvinyl formal.

Further, as a simple form of the platelet activating means, there can bementioned the inner wall of a portion of the extracorporeal bloodcirculation circuit structure (at such a portion of the circuitstructure, the inner wall is contacted by the blood during theextracorporeal blood circulation), wherein the inner wall has beenmodified into a material or condition which is capable of activatingplatelets. Examples of methods for the modification of the inner wall ofsuch a portion of the extracorporeal blood circulation circuit structureinto a material which is capable of activating platelets include amethod in which a hydrophobic property is imparted to the surface of theinner wall, and a method in which a positive electric charge is impartedto the surface of the inner wall. On the other hand, as an example ofmethods for the modification of the inner wall into a condition which iscapable of activating platelets, there can be mentioned a method inwhich the surface of the inner wall is roughened.

With respect to the manner of using an anticoagulant in theextracorporeal blood circulation method of the present invention fortreating inflammatory diseases, there is no particular limitation aslong as platelets can be activated to a specific degree that theabove-mentioned requirement (1) and/or requirement (2) is satisfied. Forexample, when 3 liters of blood is treated by extracorporeal bloodcirculation, the following methods for mixing an anticoagulant intoblood can be used. The methods include a method in which nafamostatmesilate is solely used as the anticoagulant, wherein nafamostatmesilate is continuously fed at a feeding rate of from 10 to 30 mg/hour;a method in which heparin is solely used as the anticoagulant, whereinheparin is first fed as a single shot in an amount of from 500 to 3,000units and then is continuously fed at a feeding rate of from 500 to2,000 units/hour; a method in which heparin and nafamostat mesilate areused in combination as the anticoagulant, wherein heparin is first fedas a single shot in an amount of from 500 to 3,000 units and then iscontinuously fed at a feeding rate of from 500 to 2,000 units/hour whilecontinuously feeding nafamostat mesilate at a feeding rate of from 1 to50 mg/hour; a method in which heparin and gabexate mesilate are used incombination as the anticoagulant, wherein heparin is first fed as asingle shot in an amount of from 500 to 3,000 units and then iscontinuously fed at a feeding rate of from 500 to 2,000 units/hour whilecontinuously feeding gabexate mesilate at a feeding rate of from 500 to3,000 mg/hour; and a method in which an ACD-A solution is solely used asthe anticoagulant, wherein the ACD-A solution is continuously fed at afeeding rate corresponding to 1/10 to 1/16 of the flow rate of thecollected blood. In the present invention, the term "unit" used forexpressing an amount of heparin means a unit as defined in the 12thRevised Japanese Pharmacopeia.

When the blood treating means used in the present invention has apressure drop index in the range of from 20 to 150, wherein the pressuredrop index is as defined above, it becomes extremely easy to providetreated blood which satisfies at least one requirement selected from thegroup consisting of the above-mentioned requirements (1) and (2),namely, requirement (1) of having a β-thromboglobulin concentration inthe range of from 1,000 to 20,000 ng/ml, as measured just outside of theblood outlet of the blood treating means, and requirement (2) of havinga platelet factor 4 concentration in the range of from 500 to 10,000ng/ml, as measured just outside of the blood outlet of the bloodtreating means. It is preferred that the pressure drop index is in therange of from 35 to 150, more preferably from 50 to 150, still morepreferably from 60 to 150. When the pressure drop index of the bloodtreating means is less than 20, platelets cannot be activated to asatisfactory degree and it is highly likely that any of theabove-mentioned requirements (1) and (2) cannot be satisfied, so that adesired therapeutic effect is almost not able to be achieved. Further,when the pressure drop index of the blood treating means is more than150, it is likely that platelets are activated to too great a degree,thus disadvantageously causing the coagulation system of blood to befully activated, so that the blood circulation system is clogged withcoagulated blood.

In the present invention, when platelets are activated to theabove-mentioned specific degree while removing leukocytes contained inthe collected blood to some extent, the therapeutic effect oninflammatory diseases can be further increased. Therefore, it ispreferred that, in addition to blood treating means 4 containingplatelet activating means, the extracorporeal blood circulation systemof the present invention contains a known leukocyte trapping filtercomprising a material comprised mainly of fibers, a porous material orthe like. As an example of a known leukocyte trapping filter, there canbe mentioned a filter disclosed in European Patent ApplicationPublication No. 478914 (corresponding to U.S. Pat. No. 5,362,406).

Further, it is more preferred that the platelet activating means 4A ofblood treating means 4 is also capable of removing leukocytes. This isbecause, by using platelet activating means 4A also capable of removingleukocytes, the amount of blood which is being extracorporeallycirculated can be decreased, as compared to that in the case of using aseparate leukocyte trapping filter as mentioned above which isincorporated into the system in addition to blood treating means 4containing platelet activating means 4A.

It is especially preferred that the platelet activating meansspecifically captures leukocytes from blood and is not likely to captureerythrocytes and useful protein components of plasma. Preferred specificexamples of blood treating means 4 containing such platelet activatingmeans include:

a module comprising a casing having a blood inlet and a blood outlet,and platelet activating means packed therein at a density of from 0.05to 0.5 g/cm³, wherein the platelet activating means comprises a filtermedium comprised mainly of a fiber mass, a non-woven fabric or the likehaving an average fiber diameter of from about 1 to about 10 μm;

a module comprising a casing having a blood inlet and a blood outlet,and platelet activating means packed therein, wherein the plateletactivating means comprises a filter medium comprised mainly of a porousmaterial having an average pore diameter of from 3 to 50 μm; and

a module comprising a casing having a blood inlet and a blood outlet,and platelet activating means packed therein, wherein the plateletactivating means comprises a filter medium comprised of particles havinga particle diameter of from 0.1 to 10 mm.

The blood treated by the blood treating means is returned to the patientthrough blood returning means 5 for returning the treated blood to thepatient. Examples of blood returning means for returning the treatedblood to the patient include those which are mentioned above as examplesof the means for collecting blood from a patient.

Further, in the extracorporeal blood circulation system of the presentinvention, it is also preferred that microaggregate trapping means 6 fortrapping microaggregates from the collected blood is provided betweenblood collection means 1 for collecting blood from a patient and bloodreturning means 5 for returning the treated blood to the patient.

With respect to the microaggregate trapping means, it need not beprovided in the form of an independent device, such as a drip chamberwhich has provided therein a mesh capable of removing microaggregatesfrom blood by filtration. The microaggregate trapping means may beprovided, for example, in the form of a mesh or the like which iscapable of trapping microaggregates and which is disposed in the bloodtreating means upstream of the platelet activating means, as viewed inthe flow direction of the collected blood.

As mentioned above, in the present invention, as blood treating means 4containing platelet activating means which is also capable of removingleukocytes from blood, use may be made of a module comprising a casinghaving a blood inlet and a blood outlet, and platelet activating meanspacked therein, wherein the platelet activating means comprises a filtermedium comprised of a non-woven fabric. In this case, as a preferredexample of such a filter medium, there can be mentioned a filter mediumcomprising a main filter comprised of a non-woven fabric having a smallaverage fiber diameter of from 1.0 to 5.0 μm and a rough pre-filterhaving a large average fiber diameter of from 5 to 50 μm for trappingmicroaggregates from the collected blood, wherein the rough pre-filteris disposed upstream of the main filter, as viewed in the flow directionof the collected blood.

Further, as mentioned above and as shown in FIG. 1, it is also preferredthat drip chamber 7 equipped with a mesh is provided downstream of bloodtreating means 4.

In addition, in the extracorporeal blood circulation system of thepresent invention, it is also preferred to use a plurality of bloodtreating means 4 arranged in parallel, or provide a bypass tubing so asto circumvent blood treating means 4. When a plurality of blood treatingmeans 4 arranged in parallel are used, there is an advantage in that, byallowing one or some of the plurality of blood treating means to be leftunused as a reserve, when any sign is observed wherein the treatment ofthe collected blood with blood treating means 4 causes excess activationof platelets and/or an activation of the entire blood coagulatingsystem, the blood flow route can be changed immediately so that the bodyfluid is led solely into the reserved, fresh blood treating means,thereby enabling the platelet activating means of the malfunctioningblood treating means to be washed or regenerated without interruptingthe extracorporeal blood circulation therapy. Likewise, when a bypasstubing which circumvents blood treating means 4 is provided, there is anadvantage in that, when any sign of malfunctioning is observed withrespect to blood treating means 4, the blood flow route can be changedimmediately so that the body fluid is led solely into the bypass tubing,thereby enabling the platelet activating means of the malfunctioningblood treating means to be washed and regenerated while passing the bodyfluid through the bypass tubing.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinbelow, the present invention will be described in more detail withreference to the following Examples and Comparative Examples, whichshould not be construed as limiting the scope of the present invention.

In Examples and Comparative Examples as mentioned below, each of theβ-thromboglobulin concentration in blood and the platelet factor 4concentration in blood was measured by EIA.

With respect to the terms "tender joint score", "swollen joint score"and "Ritchie Index" which are mentioned below, each of these terms iswell known in association with the methods for evaluating the conditionof a patient suffering from articular rheumatism. With respect to thetender joint score and swollen joint score, reference can be made toHamamoto et al., Medical Practice, Vol. 8, No. 7, p.1055-1059, 1991.With respect to Ritchie Index, reference can be made to Ritchie et al.,Quarterly Journal of Medicine, New Series XXXVII, No. 147, p.393-406,July 1968.

EXAMPLE 1 AND COMPARATIVE EXAMPLE 1

In each of Example 1 and Comparative Example 1, for treating a patientsuffering from ulcerative colitis, an extracorporeal blood circulationsystem as shown in FIG. 1 was prepared.

In Example 1, a non-woven fabric filter material sheet having an averagefiber diameter of about 1.7 μm, a thickness of 0.30 mm and a bulkdensity of 0.20 g/cm³ was spirally wound and laminated to form acylindrical structure having a weight of 15 g and having a hollowportion extending between both ends, thus obtaining a filter having aweight of 15 g. The obtained filter was packed in a cylindrical casinghaving an inlet and an outlet and having an inner diameter of 45 mm andan internal-space length of 160 mm, to thereby obtain filter device (α).In Example 1, the thus obtained filter device (α) was used as bloodtreating means 4 containing platelet activating means also capable ofremoving leukocytes.

In Comparative Example 1, a non-woven fabric filter material sheethaving an average fiber diameter of about 2.8 μm, a thickness of 0.42 mmand a bulk density of 0.21 g/cm³ was spirally wound and laminated toform a cylindrical structure having a weight of 11 g and having a hollowportion extending between both ends, thus obtaining a cylindrical mainfilter having a weight of 11 g. Onto the peripheral surface of theobtained main filter was spirally wound and laminated a non-woven fabricfilter material sheet having an average fiber diameter of about 12 μm, athickness of 0.21 mm and a bulk density of 0.21 g/cm³ to form aninnermost pre-filter layer having a weight of 8 g. Then, onto the formedinnermost pre-filter layer was spirally wound and laminated a non-wovenfabric filter material sheet having an average fiber diameter of about12 μm, a thickness of 0.47 mm and a bulk density of 0.14 g/cm³ to forman intermediate pre-filter layer having a weight of 4 g. Next, onto theformed intermediate pre-filter layer was spirally wound and laminated anon-woven fabric filter material sheet having an average fiber diameterof about 33 μm, a thickness of 0.22 mm and a bulk density of 0.23 g/cm³to form an outermost pre-filter layer having a weight of 4 g. Thus,there was obtained a filter comprised of a main filter and threedifferent pre-filters and having a weight of 27 g. The obtained filterwas packed in a cylindrical casing having an inlet and an outlet andhaving an inner diameter of 45 mm and an internal-space length of 160mm, to thereby obtain filter device (β). In Comparative Example 1, thethus obtained filter device (β) was used as blood treating means 4containing platelet activating means 4A also capable of removingleukocytes.

In each of filter devices (α) and (β) prepared above, the blood inlet ispositioned at one end of the casing, and the blood outlet is positionedat the other end of the casing. Each of filter devices (α) and (β) is sodesigned that blood enters the filter device through the blood inletthereof and spreads over the outer peripheral surface of the cylindricalfilter contained therein, and permeates into the interior of the filterto reach the inner peripheral surface of the filter, where the bloodgoes into the hollow portion and flows therethrough toward the bloodoutlet of the filter device, through which the blood goes out of thefilter device. With respect to each of filter devices (α) and (β), theentire surface of an end of the cylindrical filter on a side of theblood inlet of the filter device was sealed so as to prevent blood fromentering the filter through the end portion thereof.

Using individually the extracorporeal blood circulation systems in whichthe above-mentioned filter devices (α) and (β) are, respectively,incorporated as blood treating means 4, with respect to two patientssuffering from ulcerative colitis, extracorporeal blood circulation forone hour at a flow rate of 50 ml/minute was performed five times at afrequency of once per week. As the anticoagulant, an ACD-A solution wascontinuously added to the collected blood at a rate of 300 ml/hour.

The leukocyte removing ability of the platelet activating meanscontained in the blood treating means was expressed in terms of aleukocyte removal ratio (%) which was measured by a method in which twoblood samples are respectively taken, at positions upstream anddownstream of the blood treating means as viewed in the flow directionof the collected blood, 30 minutes after the start of the extracorporealblood circulation; the number of leukocytes contained in each of the twoblood samples taken before and after the treatment of the blood with theblood treating means was counted to obtain two counts of leukocytes; anda leukocyte removal ratio (%) is calculated from the two counts ofleukocytes.

Shown in Table 1 below are the results of five times of extracorporealblood circulations, namely, the β-thromboglobulin concentration in theblood, the platelet factor 4 concentration in the blood, the leukocyteremoval ratio (an average of five values obtained in the five times ofextracorporeal blood circulations), the pressure drop index of the bloodtreating means, and the degree of the alleviation of clinical symptoms(as evaluated in terms of a decrease in the number of the occurrence ofdiarrhea per day). As shown in Table 1, in Example 1, in which filterdevice (α) was used as the blood treating means, the values of theβ-thromboglobulin concentration and platelet factor 4 concentration werelarge, as compared to the corresponding values obtained in ComparativeExample 1, in which filter device (β) was used. Further, the degree ofthe alleviation of clinical symptoms in Example 1 was high, as comparedto that in Comparative Example 1. In Table 1, each of the evaluationsshown under the item "Degree of alleviation of clinical symptoms" is acomparison between the data obtained before the first time operation ofextracorporeal blood circulation and the data obtained after the fifthtime operation of extracorporeal blood circulation, and each of theβ-thromboglobulin concentration value and the platelet factor 4concentration value is an average of the five values obtained in thefive times of extracorporeal blood circulations.

                  TABLE 1                                                         ______________________________________                                                       Comparative                                                                   Example 1    Example 1                                         ______________________________________                                        β-thromboglobulin concentration                                                           755 ng/ml   5,790 ng/ml                                      Platelet factor 4 concentration                                                                      433 ng/ml                                                                                 1,730 ng/ml                                Pressure drop index                                                                                                     70                                  Leukocyte removal ratio (%)                                                                              84.0                                                                                       94.8                                  Degree of alleviation of                                                                                   Decreased from                                                                 Decreased from                                  clinical symptoms (in terms of                                                                       10 to 6                                                                                     10 to 2                                  decrease in the number of the                                                 occurrence of diarrhea per day)                                               ______________________________________                                    

EXAMPLE 2 AND COMPARATIVE EXAMPLE 2

In each of Example 2 and Comparative Example 2, for treating a patientsuffering from articular rheumatism, an extracorporeal blood circulationsystem as shown in FIG. 1 was prepared. As blood treating means 4containing platelet activating means 4A also capable of removingleukocytes, the same filter device as filter device (β) used inComparative Example 1 was used.

In each of Example 2 and Comparative Example 2, using the aboveextracorporeal blood circulation system, extracorporeal bloodcirculation for one hour at a flow rate of 50 ml/minute was performed onan articular rheumatism patient seven times at a frequency of once perweek. In Example 2, as the anticoagulant, nafamostat mesilate wascontinuously added to the collected blood at a rate of 30 mg/hour. InComparative Example 2, as the anticoagulant, an ACD-A solution wascontinuously added to the collected blood at a rate of 300 ml/hour.

Shown in Table 2 below are the results of the seven times ofextracorporeal blood circulations, namely, the β-thromboglobulinconcentration in the blood (an average of the seven values obtained inthe seven times of extracorporeal blood circulations), the plateletfactor 4 concentration in the blood (an average of seven values obtainedin the seven times of extracorporeal blood circulations), the leukocyteremoval ratio (an average of the seven values obtained in the seventimes of extracorporeal blood circulations), the pressure drop index ofthe blood treating means, and the degree of the alleviation of clinicalsymptoms (as evaluated with respect to each of tender joint score,swollen joint score and Ritchie Index, by making a comparison betweenthe data obtained before the first time operation of extracorporealblood circulation and the data obtained after the seventh time operationof extracorporeal blood circulation). As shown in Table 2, in Example 2,the values of the β-thromboglobulin concentration and platelet factor 4concentration were large, as compared to the corresponding valuesobtained in Comparative Example 2. Further, the degree of thealleviation of clinical symptoms in Example 2 was considerably high, ascompared to that in Comparative Example 2.

                  TABLE 2                                                         ______________________________________                                                     Comparative                                                                   Example 2    Example 2                                           ______________________________________                                        Anticoagulant  ACD-A solution                                                                             Nafamostat mesi-                                                           (300 ml/hour)                                                                     late (30 mg/hour)                                β-thromboglobuiin                                                                        847 ng/ml        4,818 ng/ml                                  concentration                                                                 Platelet factor 4 concentration                                                                  433 ng/ml                                                                                   1,900 ng/ml                                  Pressure drop index                                                                                  10       60                                            Leukocyte removal ratio (%)                                                                       83.5          82.8                                        Tender joint score                                                                               Decreased from                                                                         Decreased from                                                             126 to 110                                                                           119 to 63                                                              (improved by 13%)                                                                  (improved by 47%)                               Swollen joint score                                                                             Decreased from                                                                          Decreased from                                                             9 to 6                                                                              9 to 3                                                                  (improved by 33%)                                                                  (improved by 67%)                               Ritchie Index           Decreased from                                                                    Decreased from                                                             17 to 15                                                                          14 to 7                                                                   (improved by 12%)                                                                  (improved by 50%)                               ______________________________________                                    

EXAMPLE 3 AND COMPARATIVE EXAMPLE 3

In each of Example 3 and Comparative Example 3, for treating a patientsuffering from articular rheumatism, an extracorporeal blood circulationsystem as shown in FIG. 1 was prepared. As blood treating means 4containing platelet activating means 4A also capable of removingleukocytes, use was made of filter device (γ) produced by packing 60 gof cellulose acetate beads having a particle diameter of about 2 mm intoa cylindrical casing having an inlet and an outlet and having an innerdiameter of 2.5 cm and an internal-space length of 23.6 cm.

In each of Example 3 and Comparative Example 3, using the aboveextracorporeal blood circulation system, extracorporeal bloodcirculation for one hour at a flow rate of 50 ml/minute was performed onan articular rheumatism patient seven times at a frequency of once perweek. In Example 3, as the anticoagulant, heparin was continuously addedto the collected blood at a rate of 1,000 units/hour. In ComparativeExample 3, as the anticoagulant, nafamostat mesilate was continuouslyadded to the collected blood at a rate of 50 mg/hour.

Shown in Table 3 below are the results of the seven times ofextracorporeal blood circulations, namely, the β-thromboglobulinconcentration in the blood (an average of the seven values obtained inthe seven times of extracorporeal blood circulations), the plateletfactor 4 concentration in the blood (an average of the seven valuesobtained in the seven times of extracorporeal blood circulations), theleukocyte removal ratio (an average of the seven values obtained in theseven times of extracorporeal blood circulations), the pressure dropindex of the blood treating means, and the degree of the alleviation ofclinical symptoms (as evaluated with respect to each of tender jointscore, swollen joint score and Ritchie Index, by making a comparisonbetween the data obtained before the first time operation ofextracorporeal blood circulation and the data obtained after the seventhtime operation of extracorporeal blood circulation). As shown in Table3, in Example 3, the values of the β-thromboglobulin concentration andplatelet factor 4 concentration were large, as compared to thecorresponding values obtained in Comparative Example 3. Further, thedegree of the alleviation of clinical symptoms in Example 3 wasconsiderably high, as compared to that in Comparative Example 3.

                  TABLE 3                                                         ______________________________________                                                     Comparative                                                                   Example 3     Example 3                                          ______________________________________                                        Anticoagulant  Nafamostat mesi-                                                                           Heparin                                                                   late (50 mg/hour)                                                                   (1,000 units/hour)                              β-thromboglobulin                                                                         753 ng/ml    2,032 ng/ml                                     concentration                                                                 Platelet factor 4 concentration                                                                   338 ng/ml                                                                                 901 ng/ml                                     Pressure drop index                                                                                  10         60                                          Leukocyte removal ratio (%)                                                                       40.3        42.2                                          Tender joint score                                                                               Decreased from                                                                              Decreased from                                                        140 to 125                                                                           136 to 87                                                              (improved by 11%)                                                                  (improved by 36%)                               Swollen joint score                                                                             Decreased from                                                                               Decreased from                                                        8 to 6                                                                              7 to 4                                                                  (improved by 25%)                                                                  (improved by 43%)                               Ritchie Index           Decreased from                                                                         Decreased from                                                        22 to 15                                                                               19 to 10                                                             (improved by 32%)                                                                  (improved by 47%)                               ______________________________________                                    

INDUSTRIAL APPLICABILITY

When blood from a patient suffering from an inflammatory disease istreated using the extracorporeal blood circulation system or method ofthe present invention for treating inflammatory diseases so that thetreated blood satisfies the requirement (1) of having aβ-thromboglobulin concentration in the range of from 1,000 to 20,000ng/ml and/or the requirement (2) of having a platelet factor 4concentration in the range of from 500 to 10,000 ng/ml, a high degree ofalleviation of the clinical symptoms of the inflammatory disease can beachieved.

We claim:
 1. An extracorporeal blood circulation system for treatinginflammatory diseases, comprising:blood collection means for collectingblood from a patient suffering from an inflammatory disease,anticoagulant mixing means for mixing an anticoagu lant into thecollected blood, said anticoagulant having the ability to suppress anincrease in concentration of at least one platelet factor in thecollected blood, said at least one platelet factor being selected fromthe group consisting of β-thromboglobulin and platelet factor 4, bloodtransportation means for transporting the anticoagulant-containing bloodat a flow rate in the range of from 20 to 200 ml/minute, blood treatingmeans having a blood inlet and a blood outlet and containing plateletactivating means having the ability to increase, upon treatment of bloodwith said blood treating means, the concentration of said at least oneplatelet factor in the blood, and blood returning means for returningthe treated blood to said patient, said blood collection means, saidanticoagulant mixing means, said blood transportation means, said bloodtreating means and said blood returning means being liquid-tightlyconnected in this order through a tubing, wherein, when extracorporealblood circulation is conducted using said system with respect to bloodfrom said patient, said system is capable of providing treated bloodsatisfying at least one requirement selected from the group consistingof the following requirements (1) and (2):(1) having a β-thromboglobulinconcentration in the range of from 1,000 to 20,000 ng/ml, as measuredjust outside of the blood outlet of said blood treating means; and (2)having a platelet factor 4 concentration in the range of from 500 to10,000 ng/ml, as measured just outside of the blood outlet of said bloodtreating means, wherein said blood treating means has a pressure dropindex in the range of from 20 to 150, wherein said pressure drop indexis defined as a value obtained by a method in which heparin is added tobovine blood having a hematocrit value of about 40% and a total proteinof about 6.5 q/dl of plasma so that a final heparin concentrationbecomes 5 units per ml of said bovine blood; the bovine blood is flowedthrough said blood treating means at a flow rate of 50 ml/minute,wherein, before the bovine blood enters said blood treating means, thesame anticoagulant as used in a treatment of said patient with saidextracorporeal blood circulation system is mixed into said bovine bloodin the same manner as in said treatment of the patient; a blood pressuredifference (mmHg) as between the blood inlet and blood outlet of saidblood treating means is measured 20 minutes after the start of theflowing of said bovine blood; and said blood pressure difference istaken as a pressure drop index.
 2. The extracorporeal blood circulationsystem according to claim 1, wherein said blood treating means is amodule comprising a casing having a blood inlet and a blood outlet, andsaid platelet activating means packed therein, said platelet activatingmeans comprising a material comprised mainly of at least one memberselected from the group consisting of fibers, a porous material,particles, a film, a planar membrane, a hollow fiber membrane and atubular material.
 3. The extracorporeal blood circulation systemaccording to claim 1, wherein said platelet activating means is capableof removing leukocytes.
 4. An extracorporeal blood circulation methodfor treating inflammatory diseases, comprising:collecting blood from apatient suffering from an inflammatory disease, mixing an anticoagulantinto the collected blood, said anticoagulant having the ability tosuppress an increase in concentration of at least one platelet factor inthe collected blood, said at least one platelet factor being selectedfrom the group consisting of β-thromboglobulin and platelet factor 4,transporting the blood having said anticoagulant mixed thereinto, at aflow rate in the range of from 20 to 200 ml/minute to blood treatingmeans having a blood inlet and a blood outlet and containing plateletactivating means having the ability to increase, upon treatment of bloodwith said blood treating means, the concentration of said at least oneplatelet factor in the blood, passing the blood through said bloodtreating means from said inlet to said outlet to treat the blood, andreturning the treated blood to said patient, said treated bloodsatisfying at least one require ment selected from the group consistingof the following requirements (1) and (2):(1) having a β-thromboglobulinconcentration in the range of from 1,000 to 20,000 ng/ml, as measuredjust outside of the blood outlet of said blood treating means; and (2)having a platelet factor 4 concentration in the range of from 500 to10,000 ng/ml, as measured just outside of the blood outlet of said bloodtreating means, wherein said blood treating means has a pressure dropindex in the range of from 20 to 150, wherein said pressure drop indexis defined as a value obtained by a method in which heparin is added tobovine blood having a hematocrit value of about 40% and a total proteinof about 6.5 q/dl of plasma so that a final heparin concentrationbecomes 5 units per ml of said bovine blood; the bovine blood is flowedthrough said blood treating means at a flow rate of 50 ml/minute,wherein, before the bovine blood enters said blood treating means, thesame anticoagulant as used in a treatment of said patient with saidextracorporeal blood circulation system is mixed into said bovine bloodin the same manner as in said treatment of the patient; a blood pressuredifference (mmHg) as between the blood inlet and blood outlet of saidblood treating means is measured 20 minutes after the start of theflowing of said bovine blood; and said blood pressure difference istaken as a pressure drop index.
 5. The extracorporeal blood circulationmethod according to claim 4, wherein said blood treating means is amodule comprising a casing having a blood inlet and a blood outlet, andsaid platelet activating means packed therein, said platelet activatingmeans comprising a material comprised mainly of at least one memberselected from the group consisting of fibers, a porous material,particles, a film, a planar membrane, a hollow fiber membrane and atubular material.
 6. The extracorporeal blood circulation methodaccording to claim 4, wherein said platelet activating means is capableof removing leukocytes.